This is an application for a K23 award for Carolyn Calfee, M.D., a senior postdoctoral fellow in pulmonary/critical care medicine at the University of California San Francisco. Dr. Calfee is beginning her career as a young investigator in pathogenesis-oriented clinical research in acute lung injury (ALI). This K23 award will allow Dr. Calfee to achieve several goals: (1) to develop expertise in the conduct of prospective clinical studies in ALI;(2) to obtain additional training in environmental medicine and genetic epidemiology;(3) to apply advanced biostatistical methodology to clinical and biological data in order to obtain insight into disease pathogenesis;and (4) to transition to independent investigator status. To achieve these goals, Dr. Calfee has assembled a mentoring team that includes her sponsor and primary mentor, Dr. Michael Matthay, an internationally recognized expert in translational research on ALI, and two key scientific advisors, Dr. Neal Benowitz, an expert in smoking-related biomarkers, and Dr. Mark Eisner, an expert in epidemiologic studies of both ALI and secondhand smoking. The contribution of cigarette smoke exposure (CSE) to ALI susceptibility has not been evaluated in prospective, rigorous clinical studies. Dr. Calfee's preliminary data indicate that CSE may be a major risk factor for developing ALI. Dr. Calfee will first test the hypothesis that active and passive CSE increase susceptibility to ALI in an ongoing cohort of 350 major trauma patients at high risk for ALI (Aim 1). She will then test this hypothesis in a broader group of patients by using the resources of ongoing cohort studies to perform a case-control study of patients with ALI and age-matched, critically ill controls (Aim 2). Novel biomarkers of CSE will be measured to compare short and long-term exposure in cases and controls, controlling for important confounders. Dr. Calfee will then investigate the mechanistic relationship between CSE and ALI by studying key biomarkers of endothelial injury, lung epithelial injury, and disordered coagulation in patients enrolled in the case-control study (Aim 3). These studies will provide Dr. Calfee with the data needed to prepare an R01 application focused on the relationship between CSE and ALI outcomes, including the role of gene-environment interactions. Public Health Relevance: ALI remains a common and frequently fatal cause of acute respiratory failure in critically ill patients, with no specific preventative strategies or therapies available. Therefore, studying the role of CSE in the development of ALI may help develop new therapies and will provide further rationale and support for measures to eliminate active and passive CSE. (End of Abstract)